Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

Abstract

The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of "iron immunology" as the synthesis of the iron metabolism and the immune response.

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

“…The presence of HO-1 in the nuclei and mitochondria suggests HO-1 has the functions other than degradation of heme (Dunn et al 2014). HO-1 expression is controlled by its own substrate (heme) though interaction with Bach1 repressor protein (Igarashi and Watanabe-Matsui 2014). The human HO-1 gene promoter is unique due to the presence of GT repeats of varying lengths (Shibahara et al 2007).…”

Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3

“…Bcl6 represses Prdm1 by binding to its intron 5 (12). Another repressor is Bach2 (BTB and CNC homologue 2), which is a basic region-leucine zipper factor and forms heterodimers with small Maf proteins through their leucine zipper domain (1,13). The Bach2-Maf heterodimers then bind to a specific DNA element termed Maf recognition element (MARE) (14).…”

High Fractional Occupancy of a Tandem Maf Recognition Element and Its Role in Long-Range β-Globin Gene Regulation

“…This has also been shown to be true for differentiating MEL cells (32). The small Maf proteins can also interact with other proteins, like NRF1, NRF2, and NRF3 (29,49). Because they lack activation domains, p18 homodimers function as repressors (49).…”

“…The small Maf proteins can also interact with other proteins, like NRF1, NRF2, and NRF3 (29,49). Because they lack activation domains, p18 homodimers function as repressors (49). We generated two MEL cell clones derived from single cells that were stably expressing the HS2 MARE ZF-DBD.…”

“…Furthermore, it has been shown that, during the differentiation of MEL cells, NF-E2 increasingly binds to the LCR HS2 tandem MARE (32). NF-E2 (p45) and Bach1 heterodimerize with the ubiquitously expressed p18 (also referred to as small Maf) proteins (49). Several studies have implicated NF-E2 in the recruitment of RNA Pol II to the adult ␤maj-globin gene promoter (32,34).…”